Intravitreal Triple Therapy with Vancomycin, , and Moxifloxacin for Bacterial Stephen Jae Kim, MD, Kenneth Taubenslag, MD, Shriji Patel, MD

Vanderbilt University Medical Center Financial Disclosures

None Summary

• resistance is prevalent and a major healthcare concern • Intravitreal moxifloxacin (160µg) was well tolerated • Visual acuity outcomes of eyes with endophthalmitis after cataract surgery treated with intravitreal moxifloxacin in addition to standard therapy compared favorably to those in the Endophthalmitis Vitrectomy Study treated with standard therapy alone Acknowledgement

• Special thanks to Kenneth Taubenslag, MD for his primary role in this research Background

• Increasing antibiotic resistance 1 • Acute-onset bacterial endophthalmitis – vancomycin for gram-positive coverage – either ceftazidime or an for gram- negative coverage • Endophthalmitis Vitrectomy Study (EVS) – All gram-positive isolates (94.2%) were susceptible to vancomycin – 11% of gram-negative isolates (6.5%) were resistant to both and ceftazidime 2 – Gram-negative had worse visual outcomes

1. Dave SB, Toma HS, Kim SJ. Changes in ocular flora in eyes exposed to ophthalmic . Ophthalmology. 2013;120(5):937 2. Han DP, Wisniewski SR, Wilson LA, Barza M, Vine AK, Doft BH, Kelsey SF. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1196;122(1):1-17. Questions

• Is vancomycin and a 3rd or 4th generation (ceftazidime) enough coverage for causative organisms in 2020? • Is single coverage for gram-negative adequate? Moxifloxacin

• Broad-spectrum 4th generation quinolone that is active again both gram-positive and gram-negative bacteria • Inhibits DNA gyrase and topoisomerase IV, necessary to unwind bacterial DNA for replication Vancomycin Moxifloxacin

Long-term potency, sterility, and stability of vancomycin, ceftazidime, and moxifloxacin for treatment of bacterial endophthalmitis. Mehta S, Armstrong BK, Kim SJ, Toma H, West JN, Yin H, Lu P, Wayman LL, Recchia FM, Sternberg P Jr. Retina. 2011:31(7):1316-22. • Oral administration of 400 mg moxifloxacin results in intravitreal drug levels that exceeded the mean inhibitory concentration (MIC) 90 (1.2 µg/ml) of many bacteria implicated in endophthalmitis 1 • of moxifloxacin at a concentration of ≤ 160 µg/0.1 ml was nontoxic in rabbit eyes 2,3

1. Lott MN, Fuller JJ, Hancock HA, Singh J, Singh H, McGwin G Jr, Marcus DM. Vitreal penetration of oral moxifloxacin in humans. Retina. 2008;28(3):473-6. 2. Gao H, Pennesi ME, Qiao X, Iyer MN, Wu SM, Holz ER, Mieler WF. Intravitreal moxifloxacin: retinal safety study with electroretinography and histopathology in animal models. Invest Ophthalmol Vis Sci. 2006;47(4):1606-11. 3. Aydin E, Kazi AA, Peyman GA, Esfahani MR. Intravitreal toxicity of moxifloxacin. Retina. 2006;26(2):187-90. Added Coverage

Vancomycin

Triple cover gram + Ceftazidime Double cover gram -

Moxifloxacin Synergy

• “the interaction of two or more agents to produce a combined effect greater than the sum of their separate effects” • Combination of a and aminoglycoside significantly reduces the MIC of each antibiotic Mechanism of Action

• Vancomycin: inhibits synthesis – Not effective against most gram-negative bacteria • Ceftazidime: inhibits cell wall synthesis – Effective against – Ineffective against MRSA • Moxifloxacin: inhibits cell replication Purpose

• To examine visual and safety outcomes of patients with bacterial endophthalmitis treated with: – vancomycin 1mg – ceftazidime 2mg – moxifloxacin 160 µg

Long-term potency, sterility, and stability of vancomycin, ceftazidime, and moxifloxacin for treatment of bacterial endophthalmitis. Mehta S, Armstrong BK, Kim SJ, Toma H, West JN, Yin H, Lu P, Wayman LL, Recchia FM, Sternberg P Jr. Retina. 2011:31(7):1316-22. Methods

• Single-center retrospective review of all patients treated for endophthalmitis from January 2009 to August 2019 • Inclusion criteria: – Bacterial endophthalmits – Treatment with intravitreal vancomycin, ceftazidime, and moxifloxacin: “triple therapy” • Patients with less than 3 months follow-up were excluded • Patients could receive topical or systemic antibiotics and steroids at discretion of treating physician Primary Outcomes

• Percent of eyes attaining ≥ 20/200 Snellen visual acuity • Percent of eyes attaining ≥ 20/50 Snellen visual acuity • Adverse effects Overall Results

• 94 eyes met inclusion criteria • 51 of 94 eyes (54%) achieved a final visual acuity of ≥ 20/200 • 29 of 94 eyes (31%) achieved a final visual acuity of ≥ 20/50 Table 1. Baseline Characteristics All patients Post-cataract Post-injection Bleb-associated (n=94) (n=18) (n=18) (n=10) Age, y 64 (15-95) 67 (43-80) 72 (54-95) 66 (53-88) Median (range) Right eye 43 (46%) 8 (44%) 6 (33%) 8 (80%) Female 47 (50%) 11 (61%) 11 (61%) 5 (50%) Black 13 (14%) 1 (6%) 2 (11%) 6 (60%) History of Diabetes 22 (23%) 2 (11%) 6 (33%) 1 (10%)

History of Glaucoma 23 (24%) 2 (11%) 4 (22%) 10 (100%) History of AMD 14 (15%) 1 (6%) 11 (61%) 0 Days from procedure — 5 (1-80) 3 (2-7) — median (range) Visual acuity 32 (34%) 2 (11%) 2 (11%) 4 (40%) HM 32 (34%) 8 (44%) 7 (39%) 3 (30%) CF (<5/200) 17 (18%) 4 (22%) 5 (22%) 1 (10%) 13 (14%) 4 (22%) 4 (28%) 2 (20%) Intraocular pressure

0-5 1 (1%) 1 (6%) 0 0 6-25 71 (76%) 16 (88%) 12 (66%) 6 (60%) >25 22 (23%) 1 (6%) 4 (22%) 4 (40%) Subgroup Analysis

• Visual acuity survival curves were superior for patients with post-cataract endophthalmitis compared to post- injection (P < 0.005) or bleb-associated (P < 0.005)

Post-cataract

• 17 of 18 (94%) eyes with post-cataract endophthalmitis obtained ≥ 20/200 visual acuity (78% of patients achieved ≥ 20/200 in EVS)1 • 14 of 18 (77%) obtained ≥ 20/50 visual acuity (59% of patients achieved ≥ 20/50 in EVS)1

1. Results of the Endophthalmitis Vitrectomy Study: A Randomized Trial of Immediate Vitrectomy and of Intravenous Antibiotics for the Treatment of Postoperative Bacterial Endophthalmitis. Arch Ophthalmol. 1995;113(12):1479–1496. Safety of Moxifloxacin

• No cases of macular infarction • No higher rates of retinal detachment • No cases of excessive inflammation Conclusions

• Intravitreal moxifloxacin (160µg) appeared to be well tolerated • Visual acuity outcomes of post-cataract endophthalmitis group treated with triple therapy compared favorably to EVS • Addition of moxifloxacin to standard treatment with vancomycin and ceftazidime for acute bacterial endophthalmitis may be advantageous Thanks for your Attention ! Long-term potency, sterility, and stability of vancomycin, ceftazidime, and moxifloxacin for treatment of bacterial endophthalmitis. Mehta S, Armstrong BK, Kim SJ, Toma H, West JN, Yin H, Lu P, Wayman LL, Recchia FM, Sternberg P Jr. Retina. 2011:31(7):1316-22. Results of the Endophthalmitis Vitrectomy Study: A Randomized Trial of Immediate Vitrectomy and of Intravenous Antibiotics for the Treatment of Postoperative Bacterial Endophthalmitis. Arch Ophthalmol. 1995;113(12):1479–1496.